Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: Primary role for HLA-DRB1*15:01.

Abstract

Objective. Major histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations, HLA-DRB1*03:01 and DRB1*15:01 are susceptibility alleles, but C4 locus was reported to account for the association of HLA-DRB1*03:01. With respect to DRB1*15:01, strong linkage disequilibrium (LD) with a variant rs2105898T in the XL9 region, located between DRB1 and DQA1 and regulates HLA-class II expression levels, was reported; however, the causative allele remains to be determined. Leveraging the genetic background of the Japanese population, where DRB1*15:01 and DRB1*15:02 are commonly present and only DRB1*15:01 is associated with SLE, this study aimed to distinguish the genetic contribution of DRB1*15:01 and XL9 variants. Methods. Among the XL9 variants, two (rs2105898 and rs9271593) previously associated variants in the European populations and two (rs9271375 and rs9271378) which showed a trend towards association in a Japanese genome-wide association study were selected. Associations of the XL9 variants and HLA-DRB1 were examined in 442 Japanese SLE patients and 779 controls. Genotyping of the XL9 variants were performed by TaqMan SNP Genotyping Assay and direct sequencing. HLA-DRB1 alleles were determined by polymerase chain reaction-reverse sequence-specific oligonucleotide probes. Results. Among the XL9 variants, associations of rs2105898T and rs9271593C were replicated in the Japanese population. However, these associations became no longer significant when conditioned on DRB1*15:01. In contrast, the association of DRB1*15:01 remained significant after conditioning on the XL9 variants. Conclusion. In the Japanese population, DRB1*15:01 was found to be primarily associated with SLE, and to account for the apparent association of XL9 region.

Competing Interest Statement

Dr. Kawasaki has received research grants from Ichiro Kanehara Foundation, Takeda Science Foundation, and Japan College of Rheumatology, and honoraria for lectures from Chugai Pharmaceutical Co. Ltd. Dr. Tamura has received grants from Asahi Kasei Pharma, Asahi Kasei Medical, Ayumi, AbbVie, Eisai, Nippon Boehringer Ingelheim, Taisho, Tanabe Mitsubishi, and Chugai, and speaker fees from Asahi Kasei Pharma, AstraZeneca, AbbVie, Eli Lilly Japan, GlaxoSmithKline, Chugai, Novartis, Bristol Myers Squibb, and Janssen. Dr. Itoh and Dr. Kusanagi have received grants from Asahi Kasei Pharma, Eizai, Teijin Pharma, and Chugai Pharmaceutical. Dr. Itoh has received honoraria for lectures from Asahi Kasei Pharma and Abbvie. Dr. Tsuchiya has received grants from Bristol-Myers Squibb K.K., the Naito Foundation, the Uehara Memorial Foundation, and collaborative research fund from H.U. Group Research Institute G.K.. Dr. Tsuchiya has received award grants from Japan College of Rheumatology and Japan Rheumatism Foundation, and honoraria for lectures from Teijin Ltd. Other authors have no competing interest to disclose.

Funding Statement

This study was partly supported by the collaborative research fund from H.U. Group Research Institute G.K., and by award grants given to Dr. Tsuchiya from Japan College of Rheumatology and Japan Rheumatism Foundation. The funders had no role in the design, analysis, interpretation and paper writing of this study.

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I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was reviewed and approved by the of University of Tsukuba Institute of Medicine Ethics Committee (approval ID: 122(1), 123, 268). In addition, this study was also approved by the Ethics Committees of the following institutes. which participated in the collaboration and/or recruitment of the subjects: the University of Tokyo, Nara Medical University, Juntendo University and National Defense Medical College. This study was conducted in accordance with the principles of the Declaration of Helsinki and Ethical Guidelines for Human Genome/Gene Analysis Research implemented by the Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labour and Welfare, and Ministry of Economy, Trade and Industry, of Japan. Written informed consent was obtained from each participant.

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All data relevant to the study are included in the article or uploaded as Online Supplementary Materials.

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